Project Summary/Abstract The rate of opioid prescribing for patients with kidney failure treated with long-term hemodialysis (HD) is more than twice that in the general population. Even short-term and/or low-dose prescription opioids are associated with significant health risk to HD patients. A key driver of the high frequency of opioid use is the high prevalence of chronic pain in this patient population and hence, any intervention to reduce opioid use in HD patients has to include strategies to effectively manage chronic pain. Behavioral interventions such as cognitive behavioral therapy (CBT) alone or augmented by safer drugs such as transdermal buprenorphine may reduce opioid use while managing pain, but the safety and efficacy of these interventions for HD patients remains untested. We propose to close the gaps in our knowledge with a multi-center parallel group randomized controlled trial to test the efficacy of two interventions to reduce opioid use in HD patients. In this trial, 720 HD patients with significant and ongoing opioid use will be randomly assigned 1:1:1 to (1) telehealth CBT alone; (2) telehealth CBT augmented by transdermal buprenorphine; and (3) usual care, with follow-up for up to one year. We propose adapting CBT for pain to the needs of this patient population by incorporating therapy for insomnia, depression, and anxiety. Study participants will be identified by an efficient approach to pre-screening by obtaining granular data on all prescriptions filled by the patient over the preceding 365 days in any of 75,000 pharmacies nationwide. The primary outcome will be prescribed morphine milligram equivalent (MME) over the preceding 4 weeks and three patient reported outcomes, interference by pain, functional status, and quality of life, will comprise the secondary outcomes. While the primary and secondary outcomes will be assessed at six months, additional assessments will be made at 12 weeks and 1 year. Other outcomes will include other patient reported outcomes (severity of pain, depression, anxiety, and insomnia), significant events (hospitalizations, falls, altered mental status, fractures), and all-cause mortality. We also propose to follow any HD patient identified to have opioid use disorder prospectively while receiving medication assisted treatment. The Clinical Center will be led by three co-Principal Investigators that have partnered with five non-profit dialysis providers for access to a diverse group of HD patients in Albuquerque, New York, and Seattle, with a period prevalent census over 3 years of over 7000 patients. Our team has a track record of collaboration, extensive experience in conducting clinical trials in HD patients including trials of behavioral interventions and delivering CBT via telehealth, large cumulative expertise in patient-reported outcomes for HD patients and standardized blinded collection of data by computer-assisted telephone interviewing, pain management in patients with multi-morbidity, addiction medicine, and biostatistics. Our compelling preliminary data, innovative approach, community support, and partnership with dialysis providers augur a high likelihood that our Clinical Center will be able to contribute to the success of the HOPE consortium.